1. Field of the Invention
This invention relates to a process for the preparation of 4,6-dien-3-one type steroids, and more particularly to an improved process for the preparation of 4,6-dien-3-one steroids by dehydrobromination of the corresponding steroid containing a bromine atom at the 6-position as a substituent.
4,6-Dien-3-one steroids are very important due to their pharmacological activity. Such steroids are exemplified by many steroids including, for example, cyproterone acetate, chlormadinone acetate, dydrogesterone, megesterol, melengesterol, medrogestone and canrenone.
Among the above-exemplified steroids, the first six steroids are active progestins and caurenone is useful as an intermediate for spironolactone which is an antialdosteronic diuretic and hypotensive. Accordingly it is desired to develop a process for preparing 4,6-dien-3-one steroids economically.
2. Description of the Prior Art
It is well known in the art that 4,6-diene-3-one steroids can be advantageously prepared by enolating a 4-en-3-one steroid at the 3-position carbon atom to give an enolic ether having partial structural formula (I) at the 3,4,5,6-position of rings A and B of the steroid: ##STR1## wherein X.sup.1 is hydrogen, methyl, fluorine, chlorine or bromine and R.sup.1 is an alkyl having 1 to 3 carbon atoms, then brominating the enolic ether at the 6-position carbon atom to give a 6-bromosteroid having partial structural formula (II) at the same position: ##STR2## wherein X.sup.1 is as defined above and one of X.sup.1 and Br is in the .alpha.-configuration and the other is in the .beta.-configuration, and dehydrobrominating the resulting 6-bromosteroid.
Now the above-mentioned prior-art process is described in detail. The enolic ether having partial formula (I) is brominated with a brominating agent capable of providing a positive bromine ion such as N-bromosuccinimide, N-dibromodimethylhydantoin, N-dibromobenzenesulfonamide or N-bromoacetamide in acetone solvent in the presence of sodium acetate, acetic acid and water. The resulting reaction mixture is poured onto a large amount of ice-water and the precipitate is collected by filtration and dried to isolate a crude 6-bromosteroid having partial formula (II).
Alternatively, the crude 6-bromosteroid may be isolated by solvent extraction, washing with water and phase separation to remove acetic acid and sodium acetate followed by evaporation of the solvent. The 6-bromosteroid is then subjected to dehydrobromination to give the desired 4,6-dien-3-one steroid having partial formula (III) at the same position: ##STR3## wherein X.sup.1 is as defined above. The dehydrobromination is effected by dissolving the 6-bromosteroid in an aprotic solvent such as dimethylformamide or N-methylpyrrolidone and heating the solution at 100.degree. C. or above in the presence of a lithium halide such as lithium bromide and an inorganic carbonate such as lithium carbonate or calcium carbonate, or by heating the 6-bromosteroid in a tertiary organic amine such as pyridine, collidine or dimethylaniline. In general, the former dehydrobromination technique employing lithium bromide is superior to the latter.
Upon our detailed study on the above-mentioned bromination-dehydrobromination process, it has been found that the 6-bromosteroids having partial formula (II) are so unstable that when they are in solution their degradation proceeds: even at room temperature and that their crude products precipitated out of an aqueous system can be recovered in a stable form only by lyophilization. The instability of steroid 6,6-dihalides is also apparent from Japanese Patent Laid-Open No. 24666/1968 which indicates that the yields of 4,6-dien-3-one steroids do not exceed 50% even in careful laboratory-scale experiments.
Thus, if the 6-bromosteroids having partial formula (II) is unstable, the bromination-dehydrobromination process can not be applied to commercial operation.